24th November 2023

Imaging Synaptic Density

Seminal work from the 1980s shows that synaptic densities follow a trajectory similar to that of the gyrification index. Through histological staining of synaptic proteins in post-mortem human tissue, Huttenlocher and colleagues found that synapse density rapidly increased during the first year of life, whereafter it gradually fell with increasing age.

This overlay of synaptic and gyrification dynamics is no coincidence. Rather, it is believed that synaptic events determine local patterns of cortical folding. Migrating neurons synapsing with each other likely pull neighbouring areas of cortex together into gyri (with intervening sulci), whereas synaptic pruning may release such tethering connections, reducing folding.

The particularly pronounced decrease in synaptic density during childhood and adolescence is termed synaptic pruning and is considered central to appropriate neurodevelopment. Preclinical and post-mortem work has long implicated aberrant synaptic pruning in some psychiatric illnesses (such as schizophrenia and autism), but until recently, only indirect in vivo imaging approaches have been possible.

FDG PET

One such example is fluorodeoxyglucose positron emission tomography (FDG PET). Here, a radiolabeled glucose analogue is injected intravenously and crosses the blood–brain barrier, then is taken-up by highly metabolising cells before the isotope decays and resultant radiation is detected by a surrounding scanner. Thus, FDG PET signal may be considered a proxy for neuronal metabolic rate and – as neurotransmission accounts for approximately 40% of brain energy expenditure – synaptic density, too.

FDG PET studies of age-related changes in brain metabolic rate report inconsistent findings in children and adolescents. Perhaps the largest study to date included 111 individuals aged 5 months to 23 years. Here, the authors found an inverted U-shape relationship between FDG PET signal (normalised to a reference region – the cerebellum) and increasing age in >20 brain regions, broadly mapping the synaptic trajectories discussed above.

NAA MRS

Magnetic resonance spectroscopy (MRS) is the application of nuclear magnetic resonance (NMR) spectroscopy to study tissue biochemistry using MRI. MRS is commonly used to assess brain levels of the metabolite N-acetyl aspartate (NAA) – a marker of neuronal integrity whose exact function remains unclear.

It has been suggested that NAA levels may reflect synapse number and function in vivo. However, half-a-dozen MRS studies have found ongoing increases in NAA levels throughout childhood and adolescence (which may level off during adulthood and remain fairly stable during later life) – i.e. not the curvilinear trajectory of synaptic density described histologically and supported by FDG PET work. Thus, NAA may be a relatively poor proxy measure for synaptic density, whose MRS signal is heavily influenced by other neuronal factors, some of which remain unknown.

UCB-J PET

Fortunately, a recently developed PET tracer now enables us to image synapses directly. In UCB-J PET, UCB-J is labelled with a radioactive isotope of carbon (11C). It is then injected intravenously, selectively binds synaptic vesicle glycoprotein 2A (SV2A) – the cellular target of levetiracetam – and is imaged in a process similar to that described for FDG PET. As SV2A is specifically located in presynaptic axon terminals, the resultant PET signal is directly proportional to total (regional or global) synaptic density.

Interestingly, UCB-J PET studies to date show no age-related decline in regional synaptic density in healthy volunteers. However, few studies have yet been completed and only include participants >18 years old. Moreover, one UCB-J PET study did find significant reductions in synaptic density with increasing age – but in several neural networks (as defined by a sophisticated data-led approach), not in predetermined regions of interest. Meanwhile, UCB-J PET reliably tracks regional synaptic changes in illness. Consistent with prior FDG PET (and NAA MRS) work, case–control UCB-J PET studies find that cortical synaptic density is considerably reduced in schizophrenia. UCB-J PET studies also show reduced synaptic density in the hippocampus in Alzheimer’s disease and substantia nigra in Parkinson’s disease.